Abstract
Triple-negative breast cancer is the main type of breast carcinoma that causes mortality among women because of the limited treatment options and high recurrence. Chronic inflammation has been linked with the tumor microenvironment (TME) in breast cancer progression. Clinacanthus nutans (CN) has gained much attention because of its anticancer properties, but its mechanism remains unclear. We aimed to study the qualitative phytochemical content and elucidate the cytotoxicity effects of CN on human triple-negative breast cancer (TNBC), MDA-MB-231 and human macrophage-like cells such as THP-1 by using sulforhodamine B (SRB) assay. As highly metastatic cells, MDA-MB-231 cells can migrate to the distal position, the effect of CN on migration were also elucidated using the scratch assay. The CN effects on ameliorating chronic inflammation in TME were studied following the co-culture of MDA-MB-231/THP-1 macrophages. The cytokine expression levels of IL-6, IL-1β and tumor necrosis factor-alpha (TNF-α) were determined using ELISA assays. The results showed that both ethanolic and aqueous CN extracts contained alkaloid, phenol and tannin, flavonoid, terpenoid, glycoside and steroid. However, saponin was only found in the aqueous extract of CN. CN was not cytotoxic to both MDA-MB-231 and THP-1 cells. The ability of MDA-MB-231 to migrate was also not halted by CN treatment. However, CN ethanol extract decreased IL-6 at 25 μg/mL (p = 0.02) and 100 μg/mL (p = 0.03) but CN aqueous extract increased IL-6 expression at 50 μg/mL (p = 0.08) and 100 μg/mL (p = 0.02). IL-1β showed decreased expression after treated with CN ethanol and CN aqueous both at 25 μg/mL (p = 0.03). TNF-α were significantly decreased after CN ethanol treatment at concentration 25- (p = 0.001), 50- (p = 0.000) and 100 μg/mL (p = 0.000). CN aqueous extract slightly inhibited TNF-α at all 25-50- and 100 μg/mL (p = 0.001, p = 0.000, p = 0.000, respectively). Overall, CN acts by ameliorating the pro-inflammatory condition in the TME and may be a potential strategy for its anticancer mechanism on highly metastatic breast cancer condition. The major pathways that link both cancer and inflammation were NF-κB and STATs thus further study on the upstream and downstream pathways is needed to fully understand the mechanism of CN extracts in cooling the inflamed TME in breast cancer.
Highlights
Breast cancer is the leading cause of death among women in the world, in which triple-negative breast cancer (TNBC) accounts for approximately 15%–20% of all breast carcinoma [1]
This study aimed to investigate the effect of Clinacanthus nutans (CN) on human metastatic breast cancer cells such as MDA-MB-231 alone and in co-culture with human macrophage-like cells such as THP-1
Considering that CN inhibits the metastasis of cancer cells to other organs, we evaluated the effectiveness of CN in inhibiting the migration of highly metastatic breast cancer cells such as MDA-MB-231
Summary
Breast cancer is the leading cause of death among women in the world, in which triple-negative breast cancer (TNBC) accounts for approximately 15%–20% of all breast carcinoma [1]. TNBC is characterized by the negative expression of the three main breast cancer biomarkers, namely, estrogen (ER), progesterone (PR) and epidermal-growth-factor-2 (HER2) receptors. This condition is associated with rapid growth, distant metastasis and poor prognosis compared with other breast cancer subtypes [2]. The tumor microenvironment (TME) is composed of the extracellular matrix (ECM) and numerous types of stromal cells, such as endothelial and immune cells, fibroblasts and adipocytes, which play important roles in tumor progression and the response to treatment [3]. During the transition of in situ to invasive carcinoma, tumor and stromal cells secrete ECMdegrading proteases such as matrix metalloproteinases (MMPs), destructing the ECM. Targeting the TME, the immune cells, may revert the immune system into a more antitumor state [6] that could be beneficial to patients with TNBC setting
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